Systems Genetics Analysis of Sex Differences in Alzheimer's Disease

阿尔茨海默病性别差异的系统遗传学分析

• 批准号: 10887088
• 负责人: Oscar Harari
• 金额: $ 140.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10887088
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Apolipoprotein E; Atlases; Behavioral; Biological; Biological Models; Brain; Brain region; Cells; Clinical; Clinical Data; Clinical Trials; Cognitive; Consensus; Data; Data Set; Development; Disease; Disease Progression; Etiology; Female; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Variation; Genomic Segment; Genomics; Genotype; Grain; Heritability; Heterogeneity; Human; Human Genetics; Impaired cognition; Individual; Inherited; Institution; Intervention; Mediating; Methodology; Modeling; Molecular; Mus; Mutation; Neurobehavioral Manifestations; Neurobiology; Nuclear RNA; Outcome; Pathogenesis; Pathway interactions; Population; Precision therapeutics; Quantitative Trait Loci; Research; Resolution; Risk; Role; Severities; Sex Differences; Specificity; Symptoms; System; Systems Biology; Technology; The Jackson Laboratory; Therapeutic; Validation; Variant; Woman; Work; behavioral phenotyping; bioinformatics tool; candidate validation; cell type; cohort; data integration; differential expression; disease heterogeneity; familial Alzheimer disease; genetic analysis; genetic approach; genetic architecture; genetic resource; genome resource; genomic data; genomic tools; high risk; human data; human model; human tissue; humanized mouse; improved; in vivo; insight; interdisciplinary collaboration; male; metabolic phenotype; mouse genetics; mouse model; multidisciplinary; neuropathology; novel; personalized approach; personalized intervention; personalized therapeutic; presenilin-1; presenilin-2; resilience; response; segregation; sex; transcriptome sequencing; treatment response

PROJECT SUMMARY Our proposed research aims to identify sex-specific genetic drivers of neuropathologic, cognitive, and metabolic phenotypes of Alzheimer’s disease by integrating longitudinal behavioral and molecular data from AD mice with genetic, genomic and clinical data from human cohorts. We will leverage a newly generated mouse population that incorporates high-risk familial AD (FAD) mutations on a genetically diverse background (BXD panel) to identify modifiers that contribute to AD resilience in this ‘humanized’ mouse population. In parallel, we will incorporate cutting-edge single-cell omic approachs to generate a molecular atlas of human brains from carriers of FAD mutations (in APP, PSEN1 and PSEN2) and non-carriers with sporadic AD. By combining and validating analyses in both mouse and human datasets, we expect to find molecular candidates that robustly contribute to sex-specific variation in symptoms of AD. We will further validate these candidates using unparalleled in vivo mouse technology to not only empircally assess their role in sex-specific mechanisms of disease, but also to evaluate sex X genotype X treatment interactions in a subset of candidates (i.e., Apoe) to inform more personalized therapeutic approaches. The approach we propose benefits from the enhanced discovery power and value of existing human genetics resources and novel, precision AD mouse models across multiple institutions to investigate the mechanisms of sex differences in AD.

项目概要 我们提出的研究旨在确定神经病理学、认知和神经病理学的性别特异性遗传驱动因素。 通过整合纵向行为和分子数据来研究阿尔茨海默病的代谢表型 AD 小鼠具有来自人类群体的遗传、基因组和临床数据。我们将利用新生成的 在遗传多样性背景下包含高风险家族性 AD (FAD) 突变的小鼠群体 （BXD 小组）以确定有助于这种“人性化”小鼠群体 AD 恢复能力的修饰因子。在 与此同时，我们将采用尖端的单细胞组学方法来生成人类的分子图谱 来自 FAD 突变（APP、PSEN1 和 PSEN2）携带者和散发性 AD 非携带者的大脑。经过 结合并验证小鼠和人类数据集中的分析，我们期望找到分子候选者 这极大地促进了 AD 症状的性别特异性变异。我们将进一步验证这些候选人 使用无与伦比的体内小鼠技术不仅可以根据经验评估其在性别特异性中的作用 疾病机制，还可以评估候选者子集中的性别 X 基因型 X 治疗相互作用 （即 Apoe）以提供更个性化的治疗方法。我们提出的方法受益于 增强现有人类遗传资源和新型精准AD小鼠的发现能力和价值 跨多个机构的模型来研究 AD 中性别差异的机制。